DNA-encoded chemistry: enabling the deeper sampling of chemical space

DNA-encoded chemistry enables rapid and inexpensive syntheses and screening of vast chemical libraries, and is generating substantial interest and investment in the pharmaceutical industry. Here, Goodnow and colleagues provide an overview of the steps involved in the generation of DNA-encoded libraries, highlighting key applications and future directions for this technology. DNA-encoded chemical library technologies are increasingly being adopted in drug discovery for hit and lead generation. DNA-encoded chemistry enables the exploration of chemical spaces four to five orders of magnitude more deeply than is achievable by traditional high-throughput screening methods. Operation of this technology requires developing a range of capabilities including aqueous synthetic chemistry, building block acquisition, oligonucleotide conjugation, large-scale molecular biological transformations, selection methodologies, PCR, sequencing, sequence data analysis and the analysis of large chemistry spaces. This Review provides an overview of the development and applications of DNA-encoded chemistry, highlighting the challenges and future directions for the use of this technology.